Drug-seeking in response to stimuli previously associated with drug use contributes significantly to recidivism in drug-addicted individuals, as presentation of drug-associated stimuli can elicit intense craving for drug, which contributes to relapse. Drug-associated cues also act as conditioned reinforcers to maintain or establish complex drug-seeking behaviors. In animal models of addiction, drug-associated stimuli can both elicit and maintain drug-seeking behavior. Considerable research has examined neural circuits underlying the role of such drug-associated conditioned reinforcers in the maintenance of drug-seeking behavior. Significantly less research has examined neural substrates underlying the ability of drug-associated discriminative stimuli to elicit drug-seeking behavior. Furthermore, whether the neural circuits in which plasticity takes place and subsequent neural activity produces these differing effects of drug-associated cues on drug-seeking behavior overlap or are distinct is not well defined. Evidence suggests, however, that there are likely to be differences in the circuits involved. Finally, activation of molecular substrates, such as activity regulated cytoskeletal- associated protein (arc), zif268, and c-fos, thought to underlie synaptic plasticity fundamental for learning and memory, has only been examined to a very limited extent in studies investigating the role of drug-associated cues in the initiation and maintenance of drug-seeking behavior. This proposal therefore will test the hypothesis that cocaine-associated discriminative stimuli that elicit drug-seeking behavior activate molecular cascades underlying synaptic plasticity in neuronal populations that are distinct from, yet somewhat overlapping with, those in which cocaine-associated conditioned reinforcers that maintain drug-seeking behavior induce these molecules. This hypothesis will be examined using cellular compartment analysis of temporal activity with fluorescent in situ hybridization (catFISH) to assess the brain regions activated by these two types of stimuli in animals exposed to both drug-associated stimuli and whether these genes are activated in the same neuronal populations in a given brain region. Such information will allow greater understanding of systems-level and molecular substrates underlying stimulus-induced drug-seeking behavior, which should translate into improved therapeutic management of stimulus-induced relapse in drug addiction. Drug seeking in response to stimuli previously associated with drug use contributes significantly to recidivism in drug-addicted individuals, as presentation of drug-associated stimuli can elicit intense craving for drug, which contributes to relapse. This project will examine the neural circuits engaged by drug-associated stimuli that elicit and maintain drug seeking behavior and the activation of molecular substrates thought to underlie synaptic plasticity fundamental for learning and memory. The data to be obtained will provide critical, novel insight into the systems-level and molecular substrates underlying stimulus-induced drug-seeking behavior, which should translate into improved therapeutic management of stimulus-induced relapse in drug addiction. [unreadable] [unreadable] [unreadable]